Immunomodulatory Role of the Antimicrobial LL-37 Peptide in Autoimmune Diseases and Viral Infections

Pahar, Bapi; Madonna, Stefania; Das, Arpita; Albanesi, Cristina; Girolomoni, Giampiero

doi:10.3390/vaccines8030517

Cited by 84 publications

(58 citation statements)

References 126 publications

(168 reference statements)

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“…In addition, it has antiviral effects including inhibition of herpes simplex virus type one (HSV-1) replication, vaccinia virus replication, retroviral replication, and replication of some adenovirus serotypes 14 . The epidemiological evidence for a positive vitamin D-related immune effect includes many studies that feature enveloped viruses.…”

Section: Introductionmentioning

confidence: 99%

LL-37 fights SARS-CoV-2: The Vitamin D-Inducible Peptide LL-37 Inhibits Binding of SARS-CoV-2 Spike Protein to its Cellular Receptor Angiotensin Converting Enzyme 2In Vitro

Roth

Luetke

Meinberger

et al. 2020

Preprint

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Objective: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen accountable for the coronavirus disease 2019 (COVID-19) pandemic. Viral entry via binding of the receptor binding domain (RBD) located within the S1 subunit of the SARS-CoV-2 Spike (S) protein to its target receptor angiotensin converting enzyme (ACE) 2 is a key step in cell infection. The efficient transition of the virus is linked to a unique protein called open reading frame (ORF) 8. As SARS-CoV-2 infections can develop into life threatening lower respiratory syndromes, effective therapy options are urgently needed. Several publications propose vitamin D treatment, although its mode of action against COVID-19 is not fully elucidated. It is speculated that vitamin D's beneficial effects are mediated by up regulating LL-37, a well known antimicrobial peptide with antiviral effects. Methods: Recombinantly expressed SARS-CoV-2 S protein, the extended S1 subunit (S1e), the S2 subunit (S2), the receptor binding domain (RBD), and ORF8 were used for surface plasmon resonance (SPR) studies to investigate LL-37's ability to bind to SARS-CoV-2 proteins and to localize its binding site within the S protein. Binding competition studies were conducted to confirm an inhibitory action of LL-37 on the attachment of SARS-CoV-2 S protein to its entry receptor ACE2. Results: We could show that LL-37 binds to SARS-CoV-2 S protein (LL-37/S-Strep KD = 407 nM, LL-37/S-His KD = 414 nM) with the same affinity, as SARS-CoV-2 binds to hACE2 (hACE2/S-Strep KD = 374 nM, hACE2/S-His KD = 368 nM). The binding is not restricted to the RBD of the S protein, but rather distributed along the entire length of the protein. Interaction between LL-37 and ORF8 was detected with a KD of 294 nM. Further, inhibition of the binding of S-Strep (IC50 = 735 nM), S1e (IC50 = 168 nM), and RBD (IC50 = 126 nM) to hACE2 by LL-37 was demonstrated. Conclusions: We have revealed a biochemical link between vitamin D, LL-37, and COVID-19 severity. SPR analysis demonstrated that LL-37 binds to SARS-CoV-2 S protein and inhibits binding to its receptor hACE2, and most likely viral entry into the cell. This study supports the prophylactic use of vitamin D to induce LL-37 that protects from SARS-CoV-2 infection, and the therapeutic administration of vitamin D for the treatment of COVID-19 patients. Further, our results provide evidence that the direct use of LL-37 by inhalation and systemic application may reduce the severity of COVID-19.

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Section: Introductionmentioning

confidence: 99%

LL-37 fights SARS-CoV-2: The Vitamin D-Inducible Peptide LL-37 Inhibits Binding of SARS-CoV-2 Spike Protein to its Cellular Receptor Angiotensin Converting Enzyme 2In Vitro

Roth

Luetke

Meinberger

et al. 2020

Preprint

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“…HD5 has the potential to also interact with SARS-CoV-2 S1, decreasing the activity of the SARS-CoV-S2 fusion protein ( 208 ). Human beta defensin 2 (hBD-2) and cathelicidin LL-37 peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability ( ( 209 ).…”

Section: Therapeutics Strategiesmentioning

confidence: 99%

Potential Therapeutic Targets and Vaccine Development for SARS-CoV-2/COVID-19 Pandemic Management: A Review on the Recent Update

et al. 2021

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly pathogenic novel virus that has caused a massive pandemic called coronavirus disease 2019 (COVID-19) worldwide. Wuhan, a city in China became the epicenter of the outbreak of COVID-19 in December 2019. The disease was declared a pandemic globally by the World Health Organization (WHO) on 11 March 2020. SARS-CoV-2 is a beta CoV of the Coronaviridae family which usually causes respiratory symptoms that resemble common cold. Multiple countries have experienced multiple waves of the disease and scientific experts are consistently working to find answers to several unresolved questions, with the aim to find the most suitable ways to contain the virus. Furthermore, potential therapeutic strategies and vaccine development for COVID-19 management are also considered. Currently, substantial efforts have been made to develop successful and safe treatments and SARS-CoV-2 vaccines. Some vaccines, such as inactivated vaccines, nucleic acid-based, and vector-based vaccines, have entered phase 3 clinical trials. Additionally, diverse small molecule drugs, peptides and antibodies are being developed to treat COVID-19. We present here an overview of the virus interaction with the host and environment and anti-CoV therapeutic strategies; including vaccines and other methodologies, designed for prophylaxis and treatment of SARS-CoV-2 infection with the hope that this integrative analysis could help develop novel therapeutic approaches against COVID-19.

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“…This peptide has been effective against IAV [ 56 ], respiratory syncytial virus (RSV) [ 57 ], hepatitis C virus (HCV) [ 58 ], and dengue virus (DENV) [ 59 ]. The effect of vitamin D deficiency and air pollution on inhibiting LL-37 expression has been suggested to exacerbate COVID-19 [ 60 ] because LL-37 can inhibit a wide range of coated viruses [ 61 , 62 ]. However, LL-37 stimulates inflammation in the lungs after infections caused by IAV and SARS-CoV [ 47 ].…”

Section: Natural Antiviral Peptidesmentioning

confidence: 99%

Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2

Maleki

Rostamian

Madanchi

2021

Expert Review of Anti-infective Therapy

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Introduction : There are currently no specific drugs and universal vaccines for Coronavirus disease 2019 (COVID-19), hence urgent effective measures are needed to discover and develop therapeutic agents. Applying peptide therapeutics and their related compounds is a promising strategy to achieve this goal. This review is written based on the literature search using several databases, previous studies, scientific reports, our current knowledge about the antimicrobial peptides (AMPs), and our personal analyses on the potential of the antiviral peptides for the treatment of COVID-19. Areas covered : In this review, we begin with a brief description of SARS-CoV2 followed by a comprehensive description of antiviral peptides (AVPs) including natural and synthetic AMPs or AVPs and peptidomimetics. Subsequently, the structural features, mechanisms of action, limitations, and therapeutic applications of these peptides are explained. Expert opinion : Regarding the lack and the limitations of drugs against COVID-19, AMPs, AVPs, and other peptide-like compounds such as peptidomimetics have captured the attention of researchers due to their potential antiviral activities. Some of these compounds comprise unique properties and have demonstrated the potential to fight SARS-CoV2, particularly melittin, lactoferrin, enfuvirtide, and rupintrivir that have the potential to enter animal and clinical trials for the treatment of COVID-19.

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Immunomodulatory Role of the Antimicrobial LL-37 Peptide in Autoimmune Diseases and Viral Infections

Cited by 84 publications

References 126 publications

LL-37 fights SARS-CoV-2: The Vitamin D-Inducible Peptide LL-37 Inhibits Binding of SARS-CoV-2 Spike Protein to its Cellular Receptor Angiotensin Converting Enzyme 2In Vitro

LL-37 fights SARS-CoV-2: The Vitamin D-Inducible Peptide LL-37 Inhibits Binding of SARS-CoV-2 Spike Protein to its Cellular Receptor Angiotensin Converting Enzyme 2In Vitro

Potential Therapeutic Targets and Vaccine Development for SARS-CoV-2/COVID-19 Pandemic Management: A Review on the Recent Update

Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2

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